Liquid pest control formulation

ABSTRACT

The present invention relates to a liquid pest control system that includes a synthetic pyrethroid as a pest control active ingredient and an agent selected from the group consisting of purified diethylene glycol monoethyl ether, tocopherol nicotinate and tocopherol succinate, and combinations thereof, to reduce or eliminate paresthesia of the synthetic pyrethroid. The system releases the synthetic pyrethroid efficiently and uniformly. The pest control system is less irritating to the animal&#39;s skin as compared to prior art systems, particularly to small breeds of dogs. The system is useful for making liquid spot-on treatments, sprays and the like.

This patent application is a divisional of U.S. Ser. No. 12/876,122,filed Sep. 4, 2010, which claims the benefit of U.S. Provisional Ser.No. 61/249,968, filed Oct. 8, 2009. Both applications are incorporatedherein by reference in their entirety.

FIELD OF THE INVENTION

The present invention relates to a liquid pest control system thatincludes a synthetic pyrethroid as a pest control active ingredient andan agent to reduce or eliminate paresthesia of the synthetic pyrethroid.The system releases the synthetic pyrethroid efficiently and uniformly.The pest control system is less irritating to the animal's skin ascompared to prior art systems, particularly to small breeds of dogs. Thesystem is useful for making liquid spot-on treatments, sprays and thelike.

BACKGROUND OF THE INVENTION

Many pest control active ingredients cause irritation (paresthesia) towarm-blooded animals (including humans). This irritation to the skinand/or eyes of warm-blooded animals hampers the use of these pestcontrol active ingredients. This irritation factor occurs even when thepest control active ingredient is blended with polymers or in otherformulations (such as granules, dusts, dips, liquids, emulsions, etc.)wherein the active ingredient is considerably diluted.

The synthetic pyrethroid class of insecticides is known to causeparesthesia when coming into contact with the skin, with differingdegrees of paresthesia being caused by different synthetic pyrethroids.Generally, the higher the degree of paresthesia, the more active thepyrethroid is against various insects; and those having a cyano group intheir molecular structure produce a greater degree of paresthesia. Whileparesthesia is a transitory phenomenon, higher degrees of paresthesiahave been known to cause severe trauma to animals' skins when appliedthereto and have required days for the pain to end and weeks for theskin to repair. Thus, it has prevented some of the most beneficialefficacious pyrethroids from being used on animals due to theunacceptable dermatological effects produced on the animal.

Efforts to prevent or reduce the paresthesia effect of pyrethroids havebeen attempted with some success. However, in marketing thesetechnologies to the total spectrum of the dog population, it wasdiscovered that there is a small percentage of the total dog population,specifically the smallest dog breeds, that is more susceptible topyrethroid-induced paresthesia than the general population and that thisparesthesia in this group of small dogs is unacceptable.

It would be desirable to have a synthetic pyrethroid-containing productthat not only reduces but actually eliminates paresthesia, including inthe small dog breeds, and to have a liquid syntheticpyrethroid-containing product that would be suitable for treatment ofsmall animals.

SUMMARY OF THE INVENTION

The present invention is directed to a method and a composition for thecontrolled delivery of a pest control active agent or a mixture ofactive agents while reducing or eliminating the irritation of the pestcontrol active agent to warm blooded mammals, including to the smallerdog breeds such as Chihuahua, Shih Tzu, Jack Russell and other smallterriers, Papillion, Brussels Griffon, Japanese Chin, Praxsky Krysarik,and the like that are typically particularly susceptible topyrethroid-induced paresthesia. More particularly, the pest controlsystem of the invention comprises a synthetic pyrethroid as the pestcontrol active agent and an agent that reduces or eliminates paresthesia(identified herein and in the appended claims as a “paresthesia-reducingagent”) selected from the group consisting of purified diethylene glycolmonoethyl ether, tocopherol nicotinate, tocopherol succinate, andcombinations thereof.

The formulation of the invention may optionally include otheringredients as necessary or desired, depending on the particularsynthetic pyrethroid chosen and the form and intended use of the finalproduct. Such optional ingredients can include, but are not limited to,additional non-synthetic pyrethroid pesticidal active agents; systemcarriers such as water, solvents, and the like; synergists; fragrances;coloring agents; preservatives; antioxidants; light stabilizers; and thelike. Examples of the resulting liquid pest control system include, butare not limited to, a dip, a spray, or a spot-on.

The present invention is further directed to a method for reducing oreliminating the irritation to warm-blooded animals, and especially tothe small breeds of dogs, of a liquid synthetic pyrethroid in a liquidpest control system, the method comprising associating aparesthesia-reducing agent (selected from the group consisting ofpurified diethylene glycol monoethyl ether, tocopherol nicotinate,tocopherol succinate, and combinations thereof) together with thesynthetic pyrethroid in a pest control formulation, the amount of theparesthesia-reducing agent(s) present being an amount effective toreduce or eliminate the irritation of the synthetic pyrethroid to warmblooded animals. Such amount can be determined by one of ordinary skillin the art following the teachings herein without undue experimentation.

The system of the invention provides a non paresthesia-producing stableformulation that may, in one embodiment, include a high percentage ofthe irritating synthetic pyrethroid. This invention further allows for ahigh concentration of synthetic pyrethroid in a stable liquidformulation at room temperature, while reducing or eliminating anyirritation of the synthetic pyrethroid. The formulation of the inventionis effective without loss of the biological activity of the syntheticpyrethroid. This invention is particularly useful for reducing oreliminating the irritation of synthetic pyrethroids to the small dogbreeds that are susceptible to pyrethroid-induced paresthesia.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “a” and “an” mean one or more, unless otherwiseindicated.

“Paresthesia” as used herein and in the appended claims is defined asprimarily a condition that results in a feeling (burning, tingling,and/or pricking sensation) of the skin.

To “eliminate the paresthesia,” as used herein and in the appendedclaims, means that a formulation has a Paresthesia Rating of less than 1for up to at least 24 hours in the Human Ear Assay, as described in theExamples hereinbelow.

As used herein, a “paresthesia-reducing agent” is an agent that reducesor eliminates paresthesia, particularly in the small breeds of dogs, andis selected from the group consisting of purified diethylene glycolmonoethyl ether, tocopherol nicotinate and tocopherol succinate, andcombinations thereof.

The pest control active agent may be chosen from any active agent knownto cause paresthesia in warm-blooded animals, such as, but not limitedto a synthetic pyrethroid. While the invention is particularly usefulfor delivering liquid synthetic pyrethroids at high concentrations inthe formulation, the invention is not limited thereto but may also beused with synthetic pyrethroids at any concentration that results in thedesired result of reducing or eliminating the paresthetic effects of theparesthesia-causing active agent while maintaining the active agent'spesticidal effects. One or more pesticidally active agents may beincluded within the formulation of the present invention, which mayinclude active agents other than synthetic pyrethroids and active agentsthat do not cause paresthesia, as long as at least one active agent inthe formulation is a synthetic pyrethroid. Exemplary pesticides andrepellents which are effective against horn flies, face flies, stableflies, house flies, mosquitoes, lice, ticks, and mites are pyrethrin,cypermethrin, decamethrin, cyhalothrin, flumethrin, cyfluthrin,fenvalerate, deltamethrin, fempropathrin, fluvalinate, flucythrinate,cyfluthrin, alphamethrin, tralomethrin, cycloprothrin, karate,cyphenothrin (Gokilaht™), or any synthetic pyrethroid with a cyano groupin its molecular structure. In one embodiment, the pest control activeagent is a synthetic pyrethroid having a cyano group in its molecularstructure.

Many of these active agents are effective both as a pesticide and arepellent, and the activity of many is enhanced by the inclusion of asynergist. Suitable synergists are known to those of skill in the art orcan be determined without undue experimentation, examples of whichinclude but are not limited to piperonyl butoxide and N-octylbicycloheptene dicarboximide.

The second component of the composition of the present invention is aparesthesia-reducing agent selected from the group consisting ofpurified diethylene glycol monoethyl ether (CTFA/INCI Name:ethoxydiglycol), tocopherol nicotinate and tocopherol succinate, andcombinations thereof. In one embodiment, only one paresthesia-reducingagent is present in the formulation. In one embodiment, a combination oftwo of the paresthesia-reducing agents is present in the formulation. Inone embodiment, all three of the paresthesia-reducing agents are presentin the formulation.

The diethylene glycol monoethyl ether must meet the followingspecifications to be specified as “purified” for use in this invention:

Density 0.978-0.9980 refractive Index at 20° C. 1.4260-1.4280 WaterContent 0.00-0.10 Acid Value 0.00-0.10 mg KOH/g Peroxide Value 0.00-8.00mg KOH/g Boiling Point 195-210° C. Oxide Ethylene Content 0.00-1.00 ppmEther Monomethylique EG Content 0-50 ppm Ethylene Glycol Content 0-620ppm Diethylene Glycol Content 0.250 ppm Apparented Substances Total0.00-0.20%This ether is compatible with high concentrations (that is, of up toabout 30 wt % or more, or of up to about 50 wt % or more, or of up toabout 90 wt % or more) of liquid synthetic pyrethroids.

The amount of total paresthesia-reducing agent(s) in the formulationrelative to the amount of synthetic pyrethroid will be an amounteffective to reduce or eliminate the irritation or paresthesia caused bythe synthetic pyrethroid. The effective amount is easily determinable byroutine experimentation following the teachings herein. Generally, thetotal amount of paresthesia-reducing agent(s) in the formulation shouldbe at least equal to the amount of synthetic pyrethroid and, often, theamount of the paresthesia-reducing agent(s) in the formulation is doubleto many times the amount of synthetic pyrethroid in the formulation inorder to reduce the irritation value of the active agent. Thus, theratio of paresthesia-reducing agent(s) to synthetic pyrethroid in oneembodiment can be from about 1:1 to about 99.9:0.1. In one embodiment,the ratio can be from about 1:1 to about 5:1. In one embodiment, theratio can be from about 1:1 to about 2:1.

When both tocopherol nicotinate and tocopherol succinate are present inthe formulation, the ratio of nicotinate to succinate is from about 1:1to about 3:1.

To prepare pest control systems according to the invention, thesynthetic pyrethroid pest control active agent and the ether componentare mixed with other ingredients as necessary or desired, depending onthe particular active agent chosen and the form and intended use of thefinal product. The resulting formulation is then processed into thedesired pest control system.

For example, the one or more pest control agent(s) and one or moreparesthesia-reducing agents are mixed together with a suitable organicsolvent, an aqueous solvent, or mixtures thereof. The liquid carrier ischosen such that the active agent(s) together with any optionaladditional ingredients form a liquid final product.

The following examples illustrate the practice of the invention. Partsare given as percentages and temperature in degrees Fahrenheit unlessotherwise noted. “RT” is room temperature.

EXAMPLES Example 1 Manufacturing Procedure

Formulations A-LL (see, Table 1 below) were prepared as follows: Allingredients were weighed and added to a heatable vessel. The vessel wasthen heated to 140° F., and the ingredients were stirred until ahomogenous mixture was achieved. The mixture was then cooled to RT.

TABLE 1 Ingredients (wt %) Transcutol Tocopherol Tocopherol FormulationGokilaht ™* Nylar ®** Solvent{circumflex over ( )} CG^(†) Nicotinate^(#)Succinate^(#) A 42.5 2.1 — 55.4 — — B 32.5 2.1 — 65.4 — — C 22.5 2.1 —75.4 — — D 12.5 2.1 — 85.4 — — E 2.5 2.1 — 95.4 — — F 1.0 2.1 — 96.9 — —G 42.5 2.1 — 12.9 42.4 — H 32.5 2.1 — 33.0 32.4 — I 22.5 2.1 — 53.0 22.4— J 12.5 2.1 — 73.0 12.4 — K 2.5 2.1 — 90.4 5.0 — L 1.0 2.1 — 95.0 1.0 —M 42.5 2.1 — 25.4 — 30.0 N 22.5 2.1 — 60.4 — 15.0 O 2.5 2.1 — 92.9 — 2.5P 1.0 2.1 —  96.19 — 0.71 Q 42.5 2.1 — 14.6 30.4 10.4 R 32.5 2.1 — 34.523.2 7.7 S 22.5 2.1 — 54.0 16.0 5.4 T 12.5 2.1 — 73.5 8.9 3.0 U 2.5 2.1— 93.0 1.8 0.6 V 1.0 2.1 — 95.9 0.75 0.25 W 42.5 2.1 12.9 — 42.4 — X32.5 2.1 33.0 — 32.4 — Y 22.5 2.1 53.0 — 22.4 — Z 12.5 2.1 73.0 — 12.4 —AA 2.5 2.1 90.4 — 5.0 — BB 1.0 2.1 95.0 — 1.0 — CC 42.5 2.1 25.4 — —30.0 DD 22.5 2.1 60.4 — — 15.0 EE 2.5 2.1 92.9 — — 2.5 FF 1.0 2.1  96.19— — 0.71 GG 42.5 2.1 14.6 — 30.4 10.4 HH 32.5 2.1 34.5 — 23.2 7.7 II22.5 2.1 54.0 — 16.0 5.4 JJ 12.5 2.1 73.5 — 8.9 3.0 KK 2.5 2.1 93.0 —1.8 0.6 LL 1.0 2.1 95.9 — 0.75 0.25 *Gokilaht ™ Technical 94.5%(d-cyphenothrin; synthetic pyrethroid); available from MGK Company.**Nylar ® Technical 100% (insect growth regulator; comprises approx. 50wt % pyriproxyfen and approx. 50 wt % corn oil); available from MGKCompany. {circumflex over ( )}aliphatic solvent, such as Isopar M ™(available from Exxon Chemicals). ^(†)Transcutol CG is purifieddiethylene glycol monoethyl ether; supplied by Gattefossé Corp.^(#)Tocopherol Nicotinate and Tocopherol Succinate are available fromSigma-Aldrich Corporation.

Testing:

The human ear assay is capable of discriminating between the effects ofvarious formulations. Rapid penetration of the active agent in the earlobe as well as the presence of the inferior maxillary of the trigeminusnerve system of the ear lobe tend to increase the sensitivity of theassay. It has been determined that a total volume of 10 μL of aformulation with an active volume (%) adjusted to 4 μL of technicalactive and applied to a human ear lobe provides, over time, anacceptable method of rating the paresthesia of formulations.

For purposes of evaluation of the discovery of this invention and toassist in determining the useful ratios of active agent to theparesthesia-reducing agent, the following screening procedure was setup:

1. Formulations are selected for evaluation.

2. A 10 μL sample of formulation to be evaluated is pipetted onto theear lobe and left physically undisturbed. The paresthetic effect of thissample is evaluated within a 24-hour period.

3. The “Paresthesia Rating” is taken at the following time intervalsfollowing application of the formulation: 15 min, 30 min, 45 min, 1hour, and each hour thereafter to 24 hours.

4. Irritation or sensitivity values are assigned according to thefollowing scale (“Paresthesia Rating”):

0=no sensation

1=slight sensation

2=sensation/no discomfort

3=noticeable sensation

4=slight discomfort

5=noticeable discomfort

6=uncomfortable

7=very uncomfortable

8=moderate hurting

9=hurting

10=severe hurting

Formulations A-V in Table 1 were screened following this procedure andwere found to have a Paresthesia Rating (“PR”) of less than 1 at anygiven period within 24 hours and 0 at 24 hours. Formulations W and GGwere also tested and were found to have a Paresthesia Rating (“PR”) ofless than 1 at any given period within 24 hours and 0 at 24 hours.

Example 2

Formulation “G” was tested on three Shih Tzu puppies with family historyof being susceptible to cyphenothrin-induced paresthesia. The animalswere examined and found to be in good health and happy. The animals weretreated with 1.5 mL of the formulation (1.45 gm/0.655 gm cyphenothrin(0.687 gm technical Gokilaht)). Treatment was made by applying the doseto the animal's back, from the back of the neck to the back shoulders.The puppies were visually observed for signs of irritation or anyreactions to the application of the formulation. The three puppiesshowed no signs of paresthesia reactions at any time between 0 to 31hours.

Example 3

Formulation “G” was tested on two adult (2-year-old) Chihuahuasfollowing the procedure of Example 2. Neither dog showed any signs ofparesthesia reactions at 0 to 31 hours.

1. A liquid pest control formulation comprising a synthetic pyrethroidand a paresthesia-reducing agent, wherein the paresthesia-reducing agentis a combination of tocopherol succinate, tocopherol nicotinate, anddiethylene glycol monoethyl ether, and wherein the paresthesia-reducingagent is present in an amount effective to reduce or eliminate theparesthesia caused by the synthetic pyrethroid to mammals.
 2. A liquidpest control formulation of claim 1, wherein the formulation furthercomprises a pesticidally active agent that does not cause paresthesiaand is not a synthetic pyrethroid.
 3. A liquid pest control formulationaccording to claim 1 wherein the synthetic pyrethroid is present in anamount of from about 1 wt % to about 50 wt % and theparaesthesia-reducing agent is present in an amount of from about 1 wt %to about 99 wt %.
 4. A liquid pest control formulation according toclaim 1, wherein the formulation is a spot-on formulation.
 5. A liquidpest control formulation comprising a synthetic pyrethroid and aparesthesia-reducing agent, wherein the paresthesia-reducing agent is acombination of tocopherol succinate and diethylene glycol monoethylether, and wherein the paresthesia-reducing agent is present in anamount effective to reduce or eliminate the paresthesia caused by thesynthetic pyrethroid to mammals.
 6. A liquid pest control formulationaccording to claim 5 wherein the tocopherol succinate is present in anamount of from about 1 wt % to about 30 wt % and the diethylene glycolmonoethyl ether is present in an amount of from about 1 wt % to about 98wt %.
 7. A liquid pest control formulation comprising a syntheticpyrethroid and a paresthesia-reducing agent, wherein theparesthesia-reducing agent is a combination of tocopherol succinate andtocopherol nicotinate, and wherein the paresthesia-reducing agent ispresent in an amount effective to reduce or eliminate the paresthesiacaused by the synthetic pyrethroid to mammals.
 8. A liquid pest controlformulation according to claim 7 wherein the paresthesia-reducing agentis present in an amount of from about 5 wt % to about 40 wt %, the ratioof tocopherol nicotinate to tocopherol succinate in the combinationbeing from about 1:1 to about 3:1.
 9. A liquid pest control formulationcomprising a synthetic pyrethroid and a paresthesia-reducing agent,wherein the paresthesia-reducing agent is tocopherol succinate, andwherein the paresthesia-reducing agent is present in an amount effectiveto reduce or eliminate the paresthesia caused by the syntheticpyrethroid to mammals.
 10. A liquid pest control formulation comprisinga synthetic pyrethroid, a pesticidally active agent that is not asynthetic pyrethroid, and a paresthesia-reducing agent, wherein theparesthesia-reducing agent is tocopherol succinate, and wherein theparesthesia-reducing agent is present in an amount effective to reduceor eliminate the paresthesia caused by the synthetic pyrethroid tomammals.
 11. A liquid pest control formulation of claim 10, wherein thepesticidally active agent is an insect growth regulator.
 12. A methodfor reducing or eliminating paresthesia caused by a synthetic pyrethroidto mammals, the method comprising treating a mammal with a liquid pestcontrol formulation comprising a synthetic pyrethroid and aparesthesia-reducing agent, wherein the paresthesia-reducing agent istocopherol succinate, and wherein the paresthesia-reducing agent ispresent in an amount effective to reduce or eliminate the paresthesiacaused by the synthetic pyrethroid to the mammal.
 13. A method accordingto claim 13 wherein the mammal is a dog.
 14. A method according to claim14 wherein the dog is a small breed.